Synopsis

In the Netherlands, the maximum tolerable risk (MTR) and the negligible risk (NR) are spaced by a factor of 100, which can be considered as a safety factor for the combined action of chemicals. This report gives (i) an overview of Dutch standard setting procedures in general, (ii) an overview of common concepts in toxicology of mixtures, (iii) the plausibility of combined effects of compounds at low doses, (iv) an overview of strategies which can be followed in the risk evaluation of chemical mixtures and (v) an evaluation of the safety factor of 100 used for the combined action of chemicals. It is concluded that at low doses, i.e. at exposure levels at or below current standards, interactions between chemicals such as synergy and antagonism are not likely to occur. At these low doses, response addition is expected to be also absent when it is assumed that the respons to each individual chemical is zero. On the contrary, dose addition is a phenomenon that can not be excluded at low doses, even not at doses below current standards. Therefore, in the risk evaluation of mixtures, (partial) dose addition will have to be taken into account. The safety factor of 100 can be regarded as a policy tool to correct for combination toxicology in standard setting procedures. This factor should thus cover possible dose addition. To gain some insight in the value of such a factor, we calculated for each individual chemical its fractional contribution to the MTR. By classifying chemicals in groups and assuming full dose addition within a group of chemicals, the degree by which the MTR was exceeded could be calculated. We evaluated 318 individual chemicals divided into 14 groups. For all groups of chemicals a safety factor of 100 was found to be more than sufficient. In most cases a factor of 10 would have been sufficient.